Process for preparing aryl-substituted pyrazoles

ABSTRACT

The present invention relates to a process for preparing 1-aryl-substituted pyrazoles, comprising the reaction of alkoxy enones and enamino ketones with arylhydrazine derivatives to give 1-aryl-substituted dihydro-1H-pyrazoles, the further reaction thereof with elimination of water to give 1-aryl-substituted trihalomethylpyrazoles, and the further processing thereof.

The present invention relates to a process for preparing1-(aryl)-substituted pyrazoles, comprising the reaction of alkoxy enonesand enamino ketones with hydrazine derivatives to give1-(aryl)-substituted dihydro-1H-pyrazoles, the further reaction thereofwith elimination of water to give 1-(aryl)-substitutedtrihalomethylpyrazoles, and the further processing thereof.

1-(Aryl)-substituted pyrazoles and 1H-pyrazoles are valuableintermediates for preparation of anthranilamides, which can find use asinsecticides.

The literature has already described the formation of pyrazoles byreaction of 1,3-dicarbonyls or corresponding 1,3-bis-electrophilicreagents with monoalkyl- or monoarylhydrazines (Synthesis 2004, N1. pp43-52). However, it is reported that, in the case of monoalkyl- ormonoarylhydrazines, the result is a mixture of regioisomeric pyrazoles(Tetrahedron 59 (2003), 2197-2205; Martins et al., T. L. 45 (2004)4935). Attempts to obtain exclusively one regioisomer failed (JOC 2007,72822 8243-8250). Likewise described in the literature is a process forpreparing trifluoromethylpyrazoles (WO 2003/016282). Likewise describedare preparation processes for (het)aryl-substituted pyrazoles (WO2007/144100), wherein the corresponding pyrazoles are obtained byreducing diesters with DIBAL or LiAlH₄. However, very low temperaturesare required, and the use of DIBAL is uneconomic.

It is therefore an object of the present invention to provide novel,economically viable processes for preparing 1-(aryl)-substitutedpyrazole derivatives and 1-(aryl)-substituted dihydro-1H-pyrazoles,which do not have the disadvantages described above, and which arenotable for a process regime which can be performed in a particularlyefficient and simple manner even on the industrial scale.

The object was achieved in accordance with the invention by a processfor preparing 1-aryl-substituted pyrazole derivatives of the generalformula (I)

in which

-   R¹ is hydroxyl, alkoxy, aryloxy, halogen,-   R¹ is preferably hydroxyl, (C₁-C₆)alkoxy, halogen,-   R¹ is more preferably hydroxyl, (C₁-C₆)alkoxy,-   R² is hydroxyl, alkoxy, arylalkoxy, alkylthio, halogen,    O—(C═O)alkyl, O—(C═O)O-alkyl, (C═O)haloalkyl, OSO₂alkyl,    OSO₂-haloalkyl, OSO₂-aryl,-   R² is preferably hydroxyl, halogen, O—(C═O)(C₁-C₆)alkyl,-   R² is more preferably hydroxyl, O(C═O)CH₃,-   R³ is H, halogen, CN, NO₂, alkyl, cycloalkyl, haloalkyl,    halocycloalkyl, alkoxy, haloalkoxy, alkylamino, dialkylamino,    cycloalkylamino,-   R³ is preferably H, halogen, CN, NO₂, (C₁-C₆)-alkyl,    halo(C₁-C₆)-alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,-   R³ is more preferably F, chlorine, bromine, iodine, CN,    (C₁-C₄)-alkyl, halo(C₁-C₄)-alkyl, halo(C₁-C₄)alkoxy,-   R³ is most preferably fluorine, chlorine, bromine, iodine,-   R³ is especially preferably chlorine,-   Z is CH, N,-   Z is preferably and more preferably N,    characterized in that    alkoxy enones and enamino ketones of the formula (II)

in which

-   R⁴ is H, alkyl, arylalkyl, —(C═O)alkyl, (C═O)haloalkyl,    —(C═O)O-alkyl, SO₂alkyl, SO₂-haloalkyl, SO₂-aryl,-   X is fluorine, chlorine, bromine, iodine,-   R⁵ is alkoxy, dialkylamino, cycloalkylamino, thioalkyl, or is    cycloalkyl which may optionally contain 1-3 heteroatoms from the    group of O, N, S,    are reacted with arylhydrazines of the formula (III)

in which

-   R³ is H, halogen, CN, NO₂, alkyl, cycloalkyl, haloalkyl,    halocycloalkyl, alkoxy, haloalkoxy, alkylamino, dialkylamino,    cycloalkylamino,-   Z is CH, N,    to give 1-aryl-substituted dihydro-1H-pyrazoles of the formula (IV)

in which X, R³, R⁴, Z are each as defined above,the latter are optionally converted further, without precedingisolation, with elimination of water, to 1-aryl-substitutedtrihalomethylpyrazoles of the formula (V)

in which X, R³, R⁴, Z are each as defined above,these compounds of the general formula (V)are converted with addition of HCl, H₂

in which R³, R⁴, Z are each as defined above,the latter are converted, after detaching the R⁴ group, tohydroxymethylpyrazole acids of the formula (VII)

in which R³, Z are as defined above, andthe latter are converted to compounds of the formula (I)

More particularly, the inventive reaction is notable for the use ofinexpensive raw materials such as alkoxyalkylene, for examplealkoxypropene, acid chlorides and aryl hydrazines, and for a processregime which can be performed in a particularly efficient and simplemanner even on the industrial scale.

The process according to the invention can be illustrated by thefollowing scheme (I):

where X, R¹, R², R³, R⁴, R⁵, Z are each as defined above.

The conversion of a compound of the formula (VII) to a compound of theformula (I) is effected by customary methods and is illustrated by wayof example using the following scheme (II).

where R³, Z are each as defined above.Scheme (II)

General Definitions

In connection with the present invention, the term “halogens” (X),unless defined otherwise, comprises those elements which are selectedfrom the group consisting of fluorine, chlorine, bromine and iodine,preference being given to using fluorine, chlorine and bromine, andparticular preference to using fluorine and chlorine. Substituted groupsmay be mono- or polysubstituted, and the substituents may be the same ordifferent in the case of polysubstitutions.

Alkyl groups substituted by one or more halogen atoms (—X) (═haloalkylgroups) are, for example, selected from trifluoromethyl (CF₃),difluoromethyl (CHF₂), CCl₃, CFCl₂, CF₃CH₂, ClCH₂, CF₃CCl₂.

In connection with the present invention, alkyl groups, unless defineddifferently, are linear or branched hydrocarbon groups.

The definitions of alkyl and C₁-C₁₂-alkyl encompass, for example, themeanings of methyl, ethyl, n-, isopropyl, n-, iso-, sec- and t-butyl,n-pentyl, n-hexyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, n-heptyl,n-nonyl, n-decyl, n-undecyl, n-dodecyl.

In connection with the present invention, unless defined differently,cycloalkyl groups are cyclic saturated hydrocarbon groups which mayoptionally contain 1-3 heteroatoms from the group of O, N, S.

In connection with the present invention, unless defined differently,aryl radicals are C₆-C₁₀ aromatic hydrocarbon radicals, and aromatichydrocarbon radicals which may have one, two or more heteroatoms whichare selected from O, N, P and S and may optionally be substituted byfurther groups.

In connection with the present invention, unless defined differently,arylalkyl groups and arylalkoxy groups are alkyl or alkoxy groups whichare substituted by aryl groups and may have an alkylene chain.Specifically, the definition of arylalkyl encompasses, for example, themeanings of benzyl and phenylethyl, and the definition of arylalkoxy,for example, the meaning of benzyloxy.

In connection with the present invention, unless defined differently,alkylaryl groups (alkaryl groups) and alkylaryloxy groups are arylgroups or aryloxy groups which are substituted by alkyl groups and mayhave a C₁₋₈-alkylene chain and may have, in the aryl skeleton or aryloxyskeleton, one or more heteroatoms which are selected from O, N, P and S.

The inventive compounds may, if appropriate, be present as mixtures ofdifferent possible isomeric forms, especially of stereoisomers, forexample E and Z, threo and erythro, and also optical isomers, but ifappropriate also of tautomers. Both the E and the Z isomers, and alsothe threo and erythro isomers, and the optical isomers, any desiredmixtures of these isomers and the possible tautomeric forms aredisclosed and claimed.

Alkoxy Enones and Enamino Ketones of the Formula (II)

The enones used as starting materials in the performance of the processaccording to the invention are defined in general terms by the formula(II)

where X is fluorine, chlorine, bromine, iodine, preferably fluorine,chlorine or Br, more preferably chlorine,

-   R⁴ is H, alkyl, arylalkyl, (C═O)alkyl, (C═O)haloalkyl,    —(C═O)O-alkyl, SO₂alkyl, SO₂-haloalkyl, SO₂-aryl,-   R⁴ is preferably aryl(C₁-C₆)-alkyl, (C═O)(C₁-C₆)-alkyl,    (C═O)halo(C₁-C₆)-alkyl, —(C═O)O—(C₁-C₆)-alkyl, SO₂(C₁-C₆)-alkyl,    SO₂phenyl, SO₂-halo(C₁-C₆)-alkyl,-   R⁴ is more preferably (C═O)(C₁-C₆)-alkyl, (C═O)halo(C₁-C₆)-alkyl,    —(C═O)O—(C₁-C₆)-alkyl, SO₂(C₁-C₆)-alkyl,

R⁴ is most preferably (C═O)(C₁-C₆)-alkyl, (C═O)halo(C₁-C₆)-alkyl,

-   R⁴ is especially preferably (C═O)CH₃,-   R⁵ is alkoxy, dialkylamino, cycloalkylamino, thioalkyl, or is    cycloalkyl which may optionally contain 1-3 heteroatoms from the    group of O, N, S,-   R⁵ is preferably (C₁-C₆)-alkoxy, Di(C₁-C₆)-alkylamino, morpholino,    thioalkyl,-   R⁵ is more preferably (C₁-C₄)-alkoxy,-   R⁵ is most preferably methoxy.

Examples of alkoxy enones and enamino ketones of the formula (II) whichare suitable in accordance with the invention are

-   5,5,5-trichloro-2-methoxy-4-oxopent-2-en-1-yl acetate,    1,1,1-trichloro-5-hydroxy-4-methoxypent-3-en-2-one,    5-(benzyloxy)-1,1,1-trichloro-4-methoxypent-3-en-2-one,    5,5,5-trifluoro-2-methoxy-4-oxopent-2-en-1-yl acetate,    (2Z)-5,5,5-trichloro-2-methoxy-4-oxopent-2-en-1-yl trichloroacetate.

The compounds of the formula (II) are novel, with the exception of thatcompound of the formula (II) in which X is Cl, R⁴ is phenyl and R⁵ ismethoxy, which has already been described in the literature (cf.Synthesis 2001, 13, 1959).

The compounds of the formula (II) can be prepared, for example, byreacting 5-bromo-1,1,1-trihalo-4-alkoxypent-3-en-2-one with suitableO-nucleophiles under particular reaction conditions.

Arylhydrazines of the General Formula (III)

The hydrazinopyridines used according to the present invention arecompounds of the general formula (III)

in which

-   R³ is H, halogen, CN, NO₂, alkyl, cycloalkyl, haloalkyl,    halocycloalkyl, alkoxy, haloalkoxy, alkylamino, dialkylamino,    cycloalkylamino,-   R³ is preferably H, halogen, CN, NO₂, (C₁-C₆)-alkyl,    halo(C₁-C₆)-alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy,-   R³ is more preferably F, chlorine, bromine, iodine, CN,    (C₁-C₄)-alkyl, halo(C₁-C₄)-alkyl, halo(C₁-C₄)alkoxy,-   R³ is most preferably fluorine, chlorine, bromine, iodine,-   R³ is especially preferably chlorine,-   Z is CH, N,-   Z is preferably and more preferably N.

Examples of hydrazinopyridines suitable in accordance with the inventionare 3-chloro-2-hydrazinopyridine, phenylhydrazine, o- andp-chlorophenylhydrazine, nitrophenylhydrazine, O-methylphenylhydrazine.

Step (1)

In a first embodiment of the present process, alkoxy enones and enaminoketones of the formula (II) are first reacted with arylhydrazines of theformula (III). Thereafter, the intermediates formed in step (1) areconverted to the 5-trihalomethylpyrazole derivatives of the formula (V)with elimination of water (step 2).

in which Z, X, R³, R⁴ and R⁵ are each as defined above.

It has been found that, surprisingly, the reaction of alkoxy enones andenamino ketones of the formula (II) with arylhydrazines of the formula(III) proceeds regioselectively to give 1-(aryl)-dihydropyrazolols ofthe formula (IV). The second regioisomer was not observed. It is alsoknown that organic acetates, sulphonates or carbonates react withN-nucleophiles (for example amines or hydrazines) with elimination ofthe acetate group, sulphonate group or of the carbonate group to giveamides and hydrazides. Consequently, it is considered to be surprisingthat, in the case of the reaction of alkoxy enones of the formula (II)where R⁴ is (C═O)alkyl, (C═O)haloalkyl, —(C═O)O-alkyl, SO₂alkyl,SO₂-haloalkyl, SO₂-aryl with arylhydrazines of the formula (III) whichhave strong nucleophilicity, only cyclization takes place, andaryl-5-hydroxy-5-(haloalkyl)-4,5-dihydro-1H-pyrazol-3-yl derivatives ofthe formula (IV) which were unknown to date form in a high yield.

Process step (1) of the invention is performed preferably within atemperature range from −20° C. to +100° C., more preferably attemperatures of −10° C. to +80° C.

Process step (1) of the invention is generally performed under standardpressure. Alternatively, it is, however, also possible to work underreduced pressure in order to remove the water and alcohol.

The reaction time is not critical and may be selected, according to thebatch size and temperature, within a range between a few minutes andseveral hours.

In the performance of the process step of the invention, 1 mol of theenone of the formula (II) is reacted with 0.8 mol to 1.5 mol, preferably0.9 mol to 1.2 mol, more preferably with the equimolar amount, of thearylhydrazine of the formula (III).

Suitable solvents are, for example, aliphatic, alicyclic or aromatichydrocarbons, for example petroleum ether, n-hexane, n-heptane,cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, andhalogenated hydrocarbons, for example chlorobenzene, dichlorobenzene,dichloromethane, chloroform, tetrachloromethane, dichloroethane ortrichloroethane, ethers such as diethyl ether, diisopropyl ether, methyltert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran,1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles such asacetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile;amides such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylfounanilide, N-methylpyrrolidone or hexamethylphosphoramide;sulphoxides such as dimethyl sulphoxide, or sulphones such assulpholane, alcohols such as methanol, ethanol, isopropanol. Particularpreference is given to using toluene, ethanol, methyl tert-butyl ether,THF, acetonitrile. Thearyl-5-hydroxy-5-(haloalkyl)-4,5-dihydro-1H-pyrazol-3-yl] derivativesformed can be used without preceding work-up in the subsequent step (2),in which water is eliminated. In some cases, the elimination of watertakes place actually during the cyclization.

Alternatively, these intermediates can be isolated by suitable workupsteps and optionally further purification. It is then possible toeliminate water only at a later stage.

Step 2. Water Elimination

in which Z, X, R³, R⁴ are each as defined above.

For the water elimination, the following reagents are useful: H₂SO₄,CF₃COOH, PivCl, POCl₃, polyphosphoric acid, SOCl₂, (CH₃CO)₂O, (CF₃O)₂O,oxalyl chloride, phosgene and diphosgene.

Preference is given to (CF₃CO)₂O, thionyl chloride, oxalyl chloride andphosgene.

Process step (A) of the invention is preferably performed within atemperature range from −20° C. to +100° C., more preferably attemperatures of −10° C. to +70° C.

Process step (2) of the invention is generally performed under standardpressure. Alternatively, it is, however, also possible to work underreduced pressure or under elevated pressure (e.g. reaction withphosgene). It is also possible to eliminate water merely thermally.

The reaction time is not critical and may, depending on the batch sizeand temperature, be selected within a range between a few minutes andseveral hours.

In the performance of the process step of the invention, 1 mol of the3-[(alkoxy)methyl]-1-(aryl)-5-(trihaloalkyl)-4,5-dihydro-1H-pyrazol-5-olof the formula (IV) is reacted with 0.9 to 2.5 mol, preferably 1 mol to1.8 mol, more preferably with the equimolar amount, of the dewateringagent.

Suitable solvents are, for example, aliphatic, alicyclic or aromatichydrocarbons, for example petroleum ether, n-hexane, n-heptane,cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, andhalogenated hydrocarbons, for example chlorobenzene, dichlorobenzene,dichloromethane, chloroform, tetrachloromethane, dichloroethane ortrichloroethane, ethers such as diethyl ether, diisopropyl ether, methyltert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran,1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles such asacetonitrile, propionitrile, n- or isobutyronitrile or benzonitrile;ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone orcyclohexanone; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone orhexamethylphosphoramide; sulphoxides such as dimethyl sulphoxide, orsulphones such as sulpholane. Particular preference is given to usingmethyl tert-butyl ether, toluene, xylene, dichloroethane,dichloromethane, chlorobenzene, cyclohexane or methylcyclohexane, veryparticular preference to using toluene, xylene, THF, CH₂Cl₂,dichloroethane, methyl tert-butyl ether.

Steps 3 and 4

In a preferred embodiment of the process according to the invention, the1-aryl-5-(trihalomethyl)-1H-pyrazole of the formula (V) is converteddirectly to the3-(hydroxymethyl)-1-(pyridin-2-yl)-1H-pyrazole-5-carboxylic acid of theformula (VII).

in which Z, X, R³, R⁴ are each as defined above.

The reaction is generally performed under acidic or basic conditions.

Preference is given to mineral acids, for example H₂SO₄, HCl, HSO₃Cl,HF, HBr, HI, H₃PO₄, or organic acids, for example CF₃COOH,p-toluenesulphonic acid, methanesulphonic acid,trifluoromethanesulphonic acid.

The reaction can be accelerated by the addition of catalysts, forexample FeCl₃, AlCl₃, BF₃, SbCl₃, NaH₂PO₄. The reaction can be performedin water only, without addition of acid.

Basic hydrolysis is effected in the presence of organic bases such astrialkylamines, alkylpyridines, phosphazines and1,8-diazabicyclo[5.4.0]undecene (DBU), inorganic bases such as alkalimetal hydroxides, for example lithium, sodium or potassium hydroxide,alkali metal carbonates (Na₂CO₃, K₂CO₃) and acetates such as NaOAc,KOAc, LiOAc, alkoxides, for example NaOMe, NaOEt, NaOt-Bu, KOt-Bu.

The halogenation step of the invention (A) is performed preferablywithin a temperature range from 20° C. to 120° C., more preferably attemperatures of 30° C. to 110° C.

The process step (2) of the invention is generally performed understandard pressure. Alternatively, it is, however, also possible to workunder reduced pressure or under elevated pressure (e.g. reaction in anautoclave with aqueous HCl).

The reaction time may, depending on the batch size and temperature, beselected within a range between one hour and several hours.

Steps 6 and 9

In a further embodiment of the process according to the invention, theR⁴ group is first detached (step 6). Subsequently, the hydrolysis of thetrihalomethyl group is undertaken (step 9).

where Z, X and R³ are each as defined above.

The elimination of the protecting group depends on the definition of theR⁴ radical. If R⁴ is (C₁-C₆)-alkyl or benzyl, the elimination can beeffected in the presence of BBr₃, HCl, HI, Me₃SiI, PyHCl, FeCl₃, BF₃,and in the case of benzyl additionally with hydrogen in the presence ofa catalyst. Acetate, mesylate or sulphonate groups are generallyeliminated under acidic or basic conditions. Preference is given tomineral acids, for example H₂SO₄, HCl, HSO₃Cl, HF, HBr, HI, H₃PO₄, ororganic acids, for example CF₃COOH, p-toluenesulphonic acid,methanesulphonic acid, trifluoromethanesulphonic acid.

The elimination can also be performed without addition of acids or baseson heating in water.

Basic hydrolysis is effected generally with cheap inorganic bases suchas alkali metal hydroxides, e.g. lithium, sodium or potassium hydroxide,alkali metal carbonates (Na₂CO₃, K₂CO₃), and acetates such as NaOAc,KOAc, LiOAc, alkoxides, for example NaOMe, NaOEt, NaOt-Bu, KOt-Bu.Organic bases such as trialkylamines, alkylpyridines, phosphazenes and1,8-diazabicyclo[5.4.0]undecene (DBU) can also be used.

Step 8

If R⁴ is alkyl or benzyl, the CX₃ group can be converted directly to theester group. It is thus possible to convert compounds of the formula (V)directly to the compounds of the formula (I) (step 8).

where

-   X, R³, Z are each as defined above,-   R¹ is (C₁-C₆)-alkoxy,-   R¹ is preferably methoxy, ethoxy, propoxy,-   R² is (C₁-C₆)-alkoxy, aryl(C₁-C₆)-alkoxy,-   R² is preferably aryl(C₁-C₆)-alkoxy.

For these purposes, for example, alcohols are used, for examplemethanol, ethanol, propanol, or the alcohol/HCl, alcohol/FeCl₃,alcohol/H₂SO₄ or alcohol/alkoxide combinations.

Reaction step 8 can be performed in substance or in a solvent.Preference is given to performing the reaction in a solvent. Suitablesolvents are, for example, selected from the group consisting of water,aliphatic and aromatic hydrocarbons, for example n-hexane, benzene ortoluene, which may be substituted by fluorine and chlorine atoms, suchas methylene chloride, dichloroethane, fluorobenzene, chlorobenzene ordichlorobenzene; ethers, for example diethyl ether, diphenyl ether,methyl tert-butyl ether, isopropyl ethyl ether, dioxane, diglyme,dimethylglycol, dimethoxyethane (DME) or THF; nitriles such as methylnitrile, butyl nitrile or phenyl nitrile; amides such asdimethylformamide (DMF) or N-methylpyrrolidone (NMP), or mixtures ofsuch solvents, particularly suitable solvents being water, acetonitrile,dichloromethane.

If OR⁴ is O(C═O)alk, OSO₂alk (compound of the formula (V)), the CX₃group can be converted directly to the ester group. It is thereforepossible to convert the compounds of the formula (V) directly to thecompounds of the formula (I) R²═OH (step 8).

Step 7

If OR₄ is OH (compound of the formula (VIII)), the CX₃ group can beconverted directly to the ester group. It is thus possible to convertthe compounds of the formula (VIII) directly to the compounds of theformula (I) R²═OH (step 7). For these purposes, for example, alcoholsare used, for example methanol, ethanol, propanol, or the alcohol/HCl,alcohol/FeCl₃, alcohol/H₂SO₄ or alcohol/alkoxide combinations.

Step 5

The compounds of the formula (VII) used in the performance of theprocess according to the invention are converted in a two-stage processto the compounds of the formula (I).

First, the compounds of the formula (VII) are converted with ahalogenating agent to the corresponding acid halides. At the same time,the exchange of the hydroxyl group for halogen also takes place.

in which R¹ is halogen and R² is chlorine, bromine, fluorine.

To form the acid halides and to exchange hydroxyl for halogen, thefollowing reagents are suitable: SOCl₂, POCl₃, oxalyl chloride,phosgene, diphosgene, POBr₃, PBr₃, SF₄, HCF₂CF₂N(Me)₂, PI₃. Preferenceis given to SOCl₂, oxalyl chloride, POCl₃, phosgene.

The halogenation step of the invention (step 5a) is performed preferablywithin a temperature range from −20° C. to +100° C., more preferably attemperatures of −10° C. to +70° C.

The process step of the invention is generally performed under standardpressure. Alternatively, it is, however, also possible to work underreduced pressure or under elevated pressure (e.g. reaction withphosgene).

The reaction time is not critical and may, depending on the batch sizeand temperature, be selected within a range between a few minutes andseveral hours.

In the performance of the process step of the invention, 1 mol of theacid of the formula (VII) is reacted with 1.9 mol to 2.5 mol, preferably1.95 mol to 2.2 mol, more preferably with the equimolar amount (2 eq),of the chlorinating agent.

Suitable solvents are, for example, aliphatic, alicyclic or aromatichydrocarbons, for example petroleum ether, n-hexane, n-heptane,cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, andhalogenated hydrocarbons, for example chlorobenzene, dichlorobenzene,dichloromethane, chloroform, tetrachloromethane, dichloroethane ortrichloroethane, nitriles such as acetonitrile, propionitrile, n- orisobutyronitrile or benzonitrile; amides such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone orhexamethylphosphoramide. Particular preference is given to usingtoluene, xylene, chlorobenzene, n-hexane, cyclohexane ormethylcyclohexane, methylene chloride, dichloroethane, very particularpreference to using toluene, xylene, CH₂Cl₂, ClCH₂CH₂Cl.

In step 5b, the acid halides react with alcohol to form esters of theformula (I).

Preference is given to the alcohols such as methanol, ethanol, propanol,i-propanol, cyclohexanol.

The process step of the invention is preferably performed within atemperature range from −20° C. to +100° C., more preferably attemperatures of −10° C. to +40° C.

The reaction time is not critical and may, depending on the batch sizeand temperature, be selected within a range between a few minutes andseveral hours.

In the performance of the process step of the invention, 1 mol of theacid halide of the formula (VII) is reacted with 1 to 3 eq, preferably 1eq of the alcohol. The reaction can be performed in alcohol as solvents.The halogenation and reaction with alcohol are generally performed as aone-pot reaction.

The inventive compounds of the formula (I) are valuable intermediates inthe synthesis of anthranilamides (WO 2007/112893, WO 2007/144100).

PREPARATION EXAMPLES Example 15-Bromo-1,1,1-trichloro-4-methoxypent-3-en-2-one was prepared by themethod of Gerus et al., Synthesis 2001, 3, 431-436. Yield 90%. Example 25,5,5-Trichloro-2-methoxy-4-oxopent-2-en-1-yl acetate

29.6 g (0.1 mol) of 5-bromo-1,1,1-trichloro-4-methoxypent-3-en-2-one, 17g of potassium acetate, 5 g of tetrabutylammonium bromide and 8 g ofacetic acid were stirred at 40° C. in 300 ml of acetonitrile for 16 h.The mixture was concentrated under reduced pressure, and the water wasadded to the residue. The product was extracted with ethyl acetate, theorganic phase was washed with water and the solvent was removedcompletely under reduced pressure.

This gave 25.4 g (85%) of the product as a light-brown solid with the LCpurity of 97%, m.p. 53-55° C.

¹H NMR (DMSO d₆) δ: 2.05 (s, 3H), 3.85 (s, 3H), 5.2 (s, 2H), 6.1 (s, 1H)ppm. GC/MS m/Z 275.

Example 3[1-(3-Chloropyridin-2-yl-5-hydroxy-5-(trichloromethyl)-4,5-dihydro-1H-pyrazol-3-yl]methylacetate

27.5 g (0.1 mol) of 5,5,5-trichloro-2-methoxy-4-oxopent-2-en-1-ylacetate and 14.4 g (0.1 mol) of 3-chloro-2-hydrazinopyridine wereinitially charged in 200 ml of ethanol, and the mixture was stirred at25° C. for 3 h. The precipitate was filtered off and washed withcyclohexane.

This gave 34 g of the product (90% yield) as a white solid with amelting point of 105-106° C.

¹H NMR(DMSO d₆) δ: 2.07 (s, 3H), 3.30 (dt, 1H), 3.78 (dt, 1H), 4.79 (dt,1H), 4.84 (dt, 1H), 7.23 (dd, 1H), 7.95 (dd, 1H), 8.22 (dd, 1H), 9.46(br.s, 1H) ppm.

Example 41-(3-Chloropyridin-2-yl)-5-(trichloromethyl)-1H-pyrazol-3-yl]methylacetate

38.7 g of[1-(3-chloropyridin-2-yl)-5-hydroxy-5-(trichloromethyl)-4,5-dihydro-1H-pyrazol-3-yl]methylacetate were dissolved in 200 ml of methyl tert-butyl ether, and 12.6 gof oxalyl chloride were added dropwise within 2 h (vigorous evolution ofgas).

The mixture was stirred at 25° C. for a further 5 h and concentratedcompletely under reduced pressure.

This gave 36 g of the product as a viscous oil, which crystallizedthrough after approx. 10 h at room temperature. m.p. 40° C.

¹H NMR (DMSO d₆) δ: 2.0 (s, 3H), 5.1 (dd, 2H), 7.0 (s, 1H), 7.6 (dd,1H),8.1 (dd, 1H), 8.5 (dd, 1H) ppm.

Example 5[1-(3-Chloropyridin-2-yl)-5-(trichloromethyl)-1H-pyrazol-3-yl]methanol

36.9 g of1-(3-chloropyridin-2-yl)-5-(trichloromethyl)-1H-pyrazol-3-yl]methylacetate were dissolved in 100 ml of ethanol, and 20 g of NaOH (as a 40%solution in water) were added. After 1 h, the mixture was diluted with300 ml of water, and the product was filtered off, washed with water anddried.

This gave 30 g (95%) of the product as a white solid.

m.p. 109-111° C.

¹H NMR (DMSO d₆) δ: 4.55 (2H); 6.95 (1H); 7.55 (dd, 1H); 8.05 (dd, 1H);8.5 (dd, 1H) ppm.

Example 6 Hydrochloride of1-(3-chloropyridin-2-yl)-3-(hydroxymethyl)-1H-pyrazole-5-carboxylic acid

38.7 g (0.1 mol) of[1-(3-chloropyridin-2-yl)-5-(trichloromethyl)-1H-pyrazol-3-yl]methanoland 10 g of H₂SO₄ (as a 10% solution in water) were stirred at 80° C.for 3 h.

The mixture was cooled to 0° C., and the precipitate was filtered offand washed with acetonitrile and dried.

Yield 90%. m.p. 173-175° C.

¹H NMR (DMSO d₆) δ: 3.5 (b.s, 1H) 4.50, (2H); 5.2 (b. s), 6.95 (1H);7.55 (dd, 1H); 8.05 (dd, 1H); 8.5 (dd, 1H), 13 (b.s) ppm.

Example 72-[5-Carboxy-3-(hydroxymethyl)-1H-pyrazol-1-yl]-3-chloropyridiniumhydrogenchloride

The procedure is as in Example 6, except using

1-(3-chloropyridin-2-yl)-5-(trichloromethyl)-1H-pyrazol-3-yl]methylacetate.

Yield 95%. m.p. 173-175° C.

Example 83-[(Benzyloxy)methyl]-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylicacid

4.4 g of2-{3-[(benzyloxy)methyl]-5-(trichloromethyl)-1H-pyrazol-1-yl}-3-chloropyridineand 30 ml of 20% H₂SO₄ were heated at 100° C. for 24 h.

The precipitate was filtered off and washed with water. The yield was92%.

¹H NMR (CDCl₃) δ: 4.61 (2H, s); 4.63 (m, 2H), 6.97 (1H, s); 7.2-7.4 (5H,m); 7.42 (1H, m); 7.96 [(1H, d, 2 Hz.)]; 8.5 [(1H, d, 2 Hz)] ppm.

Example 91-(3-Chloropyridin-2-yl)-3-(hydroxymethyl)-1H-pyrazole-5-carboxylic acidhydrochloride

3.43 g of3-[(benzyloxy)methyl]-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylicacid and 20 ml of HCl (37.5%) were heated at 100° C. for 2 h and thenthe reaction mixture was completely concentrated under reduced pressureat 10 mbar. This gave1-(3-chloropyridin-2-yl)-3-(hydroxymethyl)-1H-pyrazole-5-carboxylic acidas the hydrochloride salt. Neutralization with NaHCO₃ afforded the freeacid as a white solid. The yield was 94% .

Example 10 Methyl 3-(chloromethyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate

1-(3-Chloropyridin-2-yl)-3-(hydroxymethyl)-1H-pyrazole-5-carboxylic acidhydrochloride 29 g (0.1 mol) was initially charged in 100 ml of toluene.24 g SOCl₂, was added in portions at 60° C. The mixture was heated at70° C. for 3 h, in the course of which the precipitate went completelyinto the solution. Methanol (30 ml) was slowly added dropwise to themixture and the solution was stirred at 30° C. for another hour.Subsequently, the solution was concentrated under reduced pressure. Thisafforded 95% of the product with a purity of 96%.

¹H NMR (CDCl₃) δ: 3.7 (3H, s); 4.7 (2H, s); 7.1 (1H, s); 7.5 (1H, m);8.05 [(1H, m)]; 8.5 [(1H, m)] ppm

Example 11 Methyl1-(2-methylphenyl)-3-(hydroxymethyl)-1H-pyrazole-5-carboxylate

30.5 g of[1-(2-methylphenyl)-5-(trichloromethyl)-1H-pyrazol-3-yl]methanol and 300ml of methanol were heated in an autoclave at 90° C. for 3 h. Methanolwas removed under reduced pressure, and the product was purified bymeans of chromatography. Yield 80%.

Analytical Characterization

¹H NMR (CD₃CN) δ: 7.4-7.2 (4H, m); 6.95 (1H, s), 4.55 (2H, s); 3.75(3H,s); 11.95 (3H, s) ppm.

Example 12 Methyl1-(3-chloropyridin-2-yl)-3-(hydroxymethyl)-1H-pyrazole-5-carboxylate

32.6 g of[1-(3-chloropyridin-2-yl)-5-(trichloromethyl)-1H-pyrazol-3-yl]methanoland 300 ml of methanol were heated in an autoclave at 90° C. for 3 h.Methanol was removed under reduced pressure, and the precipitate waswashed with water. Yield 25 g, 94%. m.p. 104° C.

Example 13 Methyl3-(chloromethyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate

Methyl1-(3-chloropyridin-2-yl)-3-(hydroxymethyl)-1H-pyrazole-5-carboxylate(26.7 g, 0.1 mol) was dissolved in 150 ml of CH₂Cl₂, and the solutionwas cooled to 5° C. SOCl₂ (0.12 mol) in 30 ml of CH₂Cl₂ was slowly addeddropwise at this temperature. The mixture was stirred at 40° C. for afurther 4 h and concentrated under reduced pressure. The product can beused further without purification.

Analytical Characterization

¹H NMR (CD₃CN) δ: 8.52 (1H,d); 8.06 (1H,d), 7.55 (1H, dd); 7.10 (1H, s);4.75 (2H,s); 3.75 (3H,s) ppm.

1. A process for preparing an aryl-substituted pyrazole of generalformula (I)

in which R¹ is hydroxyl, alkoxy, aryloxy or halogen, R² is hydroxyl,alkoxy, arylalkoxy, alkylthio, halogen, O—(C═O)alkyl, O—(C═O)O-alkyl,(C═O)haloalkyl, OSO₂alkyl, OSO₂-haloalkyl or OSO₂-aryl, R³ is halogen,CN, NO₂, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy,haloalkoxy, alkylamino, dialkylamino or cycloalkylamino, Z is CH or N,characterized in that (A) an alkoxyenone or an enaminoketone of formula(II)

in which R⁴ is H, alkyl, arylalkyl, —(C═O)alkyl, (C═O)haloalkyl,—(C═O)O-alkyl, SO₂alkyl, SO₂-haloalkyl or SO₂-aryl, X is, chlorine,bromine or iodine, R⁵ is alkoxy, dialkylamino, cycloalkylamino orthioalkyl, or is cycloalkyl which may optionally contain 1-3 heteroatomsfrom the group of O, N or S, is reacted with an arylhydrazine of theformula (III)

in which R³ is halogen, CN, NO₂, alkyl, cycloalkyl, haloalkyl,halocycloalkyl, alkoxy, haloalkoxy, alkylamino, dialkylamino orcycloalkylamino, Z is CH or N, to give a 1-aryl-substituteddihydro-1H-pyrazole of the formula (IV)

in which X, R³, R⁴ and Z are each as defined above, (B) the latter isoptionally converted further, without preceding isolation, withelimination of water, to a 1-aryl-substituted trihalomethylpyrazole ofthe formula (V)

in which X, R³, R⁴ and Z are each as defined above, (C) the compound ofthe general formula (V) is converted with addition of HC1, H₂SO₄ or abase, to a pyrazolecarboxylic acid of the formula (VI)

in which R³, R⁴ and Z are each as defined above, (D) the latter isconverted, after detaching the R⁴ group, to a hydroxymethylpyrazole acidof the formula (VII)

in which R³ and Z are as defined above, and (E) the latter is convertedto a compound of the formula (I)


2. The process according to claim 1, characterized in that R¹ ishydroxyl, (C₁-C₆)-alkoxy or halogen, R² is hydroxyl, halogen orO—(C═O)(C₁-C₆)alkyl, R³ is halogen, CN, NO₂, (C₁-C₆)-alkyl,halo(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or halo(C₁-C₆)alkoxy, X is chlorine orbromine, Z is N, R⁴ is aryl(C₁-C₆)-alkyl, (C═O)(C₁-C₆)-alkyl, (C═O)halo(C₁-C₆)-alkyl, —(C═O)O—(C₁-C₆)-alkyl, SO₂(C₁-C₆)-alkyl, SO₂phenylor —SO₂-halo(C₁-C₆)-alkyl, R⁵ is (C₁-C₆)-alkoxy, di(C₁-C₆)-alkylamino,morpholino or thioalkyl.
 3. The process according to claims 1 or 2,characterized in that R¹ is (C₁-C₆)alkoxy or hydroxyl, R² is hydroxyl orC(═O)CH₃, R³ is chlorine, R⁴ is (C═O)CH₃, R⁵ is methoxy, X is chlorine,Z is N.
 4. The method according to claim 1 wherein X is chlorine.
 5. Themethod according to claim 2 wherein X is chlorine.
 6. The process ofclaim 1, wherein R¹ is alkoxy.
 7. The process of claim 1, wherein R¹ ishydroxyl.
 8. The process of claim 1, wherein R¹ is aryloxy.
 9. Theprocess of claim 1, wherein R¹ is halogen.
 10. The process of claim 1,wherein Z is N.
 11. The process of claim 1, wherein Z is CH.
 12. Theprocess of claim 1, wherein R³ is chlorine.
 13. The process of claim 1,wherein R² is hydroxyl.
 14. The process of claim 1, wherein R² isO(C^(═O)CH) ₃.
 15. The process of claim 1, wherein R² is halogen. 16.The process of claim 1, wherein the alkoxyenone or enaminoketone offormula (II) is reacted with the arylhydrazine of formula (III) at atemperature ranging from -20 ° C. to 25 ° C.